Page 221 - Academic Press Encyclopedia of Physical Science and Technology 3rd BioTechnology

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Encyclopedia of Physical Science and Technology EN011J-141 July 31, 2001 15:14

798 Pharmaceuticals, Controlled Release of

inhalation, or in a long-acting injectable formulation. Al- This simple change, by improving patient compliance and
liances between these technology providers and the phar- producing a more controlled constant blood level, has pro-
maceutical companies producing the protein/peptide ac- duced measurable improvements in efficacy and reduced
tive agents increase the likelihood that these novel drug toxicity for many drugs. Many oral controlled release for-
formulations will reach the marketplace. mulations are designed to produce a relatively low drug
Controlled drug delivery has a record of success in delivery rate for the first 1–3 hr while the formulation is
the pharmaceutical industry and can offer a high return in the stomach, followed by prolonged controlled release
on capital investment. Some relatively low-budget devel- of the drug once the formulation has reached the GI tract.
opment programs, which have enabled existing, effective Thisavoidschemicaldegradationofthedrugintheaggres-
drugs to be administered to the patient by controlled re- sive environment of the stomach. This type of delivery is,
lease technology, have been very successful; examples in- for example, particularly important for polypeptide drugs
clude Lupron Depot (leuprolide, a hypothalamic releasing which are rapidly and completely destroyed if delivered to
hormone used for the suppression of testosterone in the the stomach. Delivery to the GI tract is also done to achieve
treatment of malignant neoplasms of the prostate), Pro- local delivery of the drug, such as the anti-inflammatory
cardia XL (nifedipine, a calcium channel blocker used for Mesalazine for irritable bowel disease and ulcerative
the treatment of hypertension and angina), and Cardizem colitis.
CD (diltiazem, a calcium channel blocker with properties The precursors of today’s controlled release oral for-
similar to nifedipine). These are all billion-dollar products mulations were enteric tablets based on various wax ma-
that employ controlled release or delivery techniques. To trices designed to circumvent degradation in the stomach.
develop a new chemical entity through to regulatory ap- Enteric formulations were later improved by using new,
proval in the mid-1990s took, on average, 10–12 years more reliable polymers. By the mid-1970s, the first oral
and cost about $300–600 million. In contrast, an existing controlled drug delivery systems began to appear. Two im-
drug can be reformulated into an innovative drug delivery portant delivery technologies developed at that time were
system in 5–7 years at a cost of about $20–$100 million. Alza’s Oros osmotic controlled release system and Elan’s
Interestingly, there are also recent examples in which con- Sodas multiparticulate system. Elan’s Sodas system con-
trolled release is no longer a simple reformulation of an sisted of large numbers of micropellets, each designed to
old drug. For example, new drugs are being developed and release a microdose of drug by diffusion from a matrix
marketed for the first time as controlled release products. at a predetermined rate. By blending pellets with differ-
Some of these drugs might not have reached the market ent release profiles, the overall target rate was achieved.
except for controlled release technology—felodipine and Since then, a wide variety of other oral formulations us-
omeprazole are examples. ing osmosis and diffusion have been produced, as well
as slow-release bioerodible tablets, ion exchange beads,
multiple-layer tablets, and others.
A. Oral Formulations
If the drug is relatively water-soluble, osmotic or sim-
The oral route is by far the most common and convenient ple table formulations are often used to achieve controlled
method of delivering drugs to the body. Unfortunately, delivery. However, with more-insoluble drugs, release of
the method has a number of problems that interfere with the complete dosage from a single tablet in an 8- to 12-hr
effective drug delivery. First, a drug taken by mouth is period may be difficult. For such drugs, a microencapsu-
immediately exposed to low-pH stomach acids containing lated or granulated form of the drug is enclosed in a gelatin
high concentrations of digestive enzymes. Many drugs are capsule. Microencapsulation exposes a much greater sur-
chemically degraded or enzymatically metabolized in the face area of the device to interact with the body, so drugs
stomach before they are absorbed. Drugs that are absorbed that dissolve and diffuse slowly can still be completely re-
then enter the portal circulation and may be destroyed leased in an 8- to 12-hr period. Drugs can be microencap-
by the first-pass metabolism in the liver described earlier. sulated by physical and chemical methods. Physical meth-
Controlled release is a method of avoiding these problems. ods include encapsulation by pan coating, gravity flow,
The typical transit time of material through the GI tract centrifugation, and fluid bed coating. Chemical microen-
is 12–18 hr, so most controlled release oral formulations capsulation normally involves a two-step process called
are designed to deliver their loading of drug over a 6- to coacervation. Drug particles or droplets of drug solution
15-hr period. In this way the action of short-half-life drugs are first suspended in a polymer solution. Precipitation
or rapidly absorbed drugs can be spread over a prolonged of the polymer from solution is then caused by, for ex-
period. Drugs that might require dosing two or three times ample, changing the temperature or adding a nonsolvent.
a day to achieve relatively uniform and nontoxic blood The polymer then coats the drug particles to form the
levels can then be dispensed as a single once-a-day tablet. microcapsule.